Skip to main content
SpringerLink
Log in

The Yin and Yang of copper during infection

  • Minireview
  • Published:
JBIC Journal of Biological Inorganic Chemistry Aims and scope Submit manuscript

Abstract

Copper is an essential micronutrient for both pathogens and the animal hosts they infect. However, copper can also be toxic in cells due to its redox properties and ability to disrupt active sites of metalloproteins, such as Fe–S enzymes. Through these toxic properties, copper is an effective antimicrobial agent and an emerging concept in innate immunity is that the animal host intentionally exploits copper toxicity in antimicrobial weaponry. In particular, macrophages can attack invading microbes with high copper and this metal is also elevated at sites of lung infection. In addition, copper levels in serum rise during infection with a wide array of pathogens. To defend against this toxic copper, the microbial intruder is equipped with a battery of copper detoxification defenses that promote survival in the host, including copper exporting ATPases and copper binding metallothioneins. However, it is important to remember that copper is also an essential nutrient for microbial pathogens and serves as important cofactor for enzymes such as cytochrome c oxidase for respiration, superoxide dismutase for anti-oxidant defense and multi-copper oxidases that act on metals and organic substrates. We therefore posit that the animal host can also thwart pathogen growth by limiting their copper nutrients, similar to the well-documented nutritional immunity effects for starving microbes of essential zinc, manganese and iron micronutrients. This review provides both sides of the copper story and evaluates how the host can exploit either copper-the-toxin or copper-the-nutrient in antimicrobial tactics at the host-pathogen battleground.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

COX:

Cytochrome oxidase

MT:

Metallothioneins

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

References

  1. Solomon EI, Heppner DE, Johnston EM, Ginsbach JW, Cirera J, Qayyum M, Kieber-Emmons MT, Kjaergaard CH, Hadt RG, Tian L (2014) Chem Rev 114:3659–3853. doi:10.1021/cr400327t

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Pham AN, Xing GW, Miller CJ, Waite TD (2013) J Catal 301:54–64. doi:10.1016/j.jcat.2013.01.025

    Article  CAS  Google Scholar 

  3. Macomber L, Imlay JA (2009) Proc Natl Acad Sci USA 106:8344–8349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Barry AN, Shinde U, Lutsenko S (2010) J Biol Inorg Chem 15:47–59

    Article  CAS  PubMed  Google Scholar 

  5. Lutsenko S, Barnes NL, Bartee MY, Dmitriev OY (2007) Physiol Rev 87:1011–1046. doi:10.1152/physrev.00004.2006

    Article  CAS  PubMed  Google Scholar 

  6. Kaplan JH, Lutsenko S (2009) J Biol Chem 284:25461–25465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Madsen E, Gitlin JD (2007) Curr Opin Gastroenterol 23:187–192

    Article  CAS  PubMed  Google Scholar 

  8. Suzuki M, Gitlin JD (1999) Pediatr Int 41:436–442

    Article  CAS  PubMed  Google Scholar 

  9. Scheiber I, Dringen R, Mercer JF (2013) Met Ions Life Sci 13:359–387. doi:10.1007/978-94-007-7500-8_11

    Article  PubMed  Google Scholar 

  10. Weinberg ED (1975) JAMA 231:39–41

    Article  CAS  PubMed  Google Scholar 

  11. Kehl-Fie TE, Skaar EP (2010) Curr Opin Chem Biol 14:218–224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cassat JE, Skaar EP (2013) Cell Host Microbe 13:509–519. doi:10.1016/j.chom.2013.04.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kaplan J, Ward DM, De Domenico I (2011) Int J Hematol 93:14–20. doi:10.1007/s12185-010-0760-0

    Article  CAS  PubMed  Google Scholar 

  14. Correnti C, Strong RK (2012) J Biol Chem 287:13524–13531 (pii:R111.311829). doi: 10.1074/jbc.R111.311829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Clifton MC, Corrent C, Strong RK (2009) Biometals 22:557–564. doi:10.1007/s10534-009-9207-6

    Article  CAS  PubMed  Google Scholar 

  16. Damo SM, Kehl-Fie TE, Sugitani N, Holt ME, Rathi S, Murphy WJ, Zhang Y, Betz C, Hench L, Fritz G, Skaar EP, Chazin WJ (2013) Proc Natl Acad Sci USA. doi:10.1073/pnas.1220341110

    PubMed  PubMed Central  Google Scholar 

  17. Nakashige TG, Zhang B, Krebs C, Nolan EM (2015) Nat Chem Biol 11:765–771. doi:10.1038/nchembio.1891

    Article  CAS  PubMed  Google Scholar 

  18. Stafford SL, Bokil NJ, Achard ME, Kapetanovic R, Schembri MA, McEwan AG, Sweet MJ (2013) Biosci Rep 33:e00049. doi:10.1042/BSR20130014

  19. Chaturvedi KS, Henderson JP (2014) Front Cell Infect Microbiol 4:3. doi:10.3389/fcimb.2014.00003

    Article  PubMed  PubMed Central  Google Scholar 

  20. Festa RA, Thiele DJ (2012) PLoS Pathog 8:e1002887. doi:10.1371/journal.ppat.1002887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Garcia-Santamarina S, Thiele DJ (2015) J Biol Chem. doi:10.1074/jbc.R115.649129

    PubMed  Google Scholar 

  22. Hodgkinson VL, Petris MJ (2012) J Biol Chem. doi:10.1074/jbc.R111.316406

    PubMed  PubMed Central  Google Scholar 

  23. Ladomersky E, Petris MJ (2015) Metallomics 7:957–964. doi:10.1039/c4mt00327f

    Article  CAS  PubMed  Google Scholar 

  24. Samanovic MI, Ding C, Thiele DJ, Darwin KH (2012) Cell Host Microbe 11:106–115. doi:10.1016/j.chom.2012.01.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Fu Y, Chang FM, Giedroc DP (2014) Acc Chem Res. doi:10.1021/ar500300n

    PubMed Central  Google Scholar 

  26. Dollwet HHA, Sorenson JRJ (1985) Trace Elem Med 2:80–87

    Google Scholar 

  27. Casey AL, Adams D, Karpanen TJ, Lambert PA, Cookson BD, Nightingale P, Miruszenko L, Shillam R, Christian P, Elliott TS (2010) J Hosp Infect 74:72–77. doi:10.1016/j.jhin.2009.08.018

    Article  CAS  PubMed  Google Scholar 

  28. Michels HT, Keevil CW, Salgado CD, Schmidt MG (2015) HERD 9(64–79):1937. doi:10.1177/1937586715592650

    Google Scholar 

  29. Grass G, Rensing C, Solioz M (2011) Appl Environ Microbiol 77:1541–1547. doi:10.1128/AEM.02766-10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Festa RA, Helsel ME, Franz KJ, Thiele DJ (2014) Chem Biol 21:977–987. doi:10.1016/j.chembiol.2014.06.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cavet JS (2014) Chem Biol 21:921–922. doi:10.1016/j.chembiol.2014.07.011

    Article  CAS  PubMed  Google Scholar 

  32. Cha J, Cooksey SA (1991) Proc Natl Acad Sci USA 88:8915–8919

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wagner D, Maser J, Lai B, Cai Z, Barry CE 3rd, Honer ZU, Bentrup K, Russell DG, Bermudez LE (2005) J Immunol 174:1491–1500

    Article  CAS  PubMed  Google Scholar 

  34. White C, Lee J, Kambe T, Fritsche K, Petris MJ (2009) J Biol Chem 284:33949–33956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Osman D, Waldron KJ, Denton H, Taylor CM, Grant AJ, Mastroeni P, Robinson NJ, Cavet JS (2010) J Biol Chem 285:25259–25268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Achard ME, Stafford SL, Bokil NJ, Chartres J, Bernhardt PV, Schembri MA, Sweet MJ, McEwan AG (2012) Biochem J. doi:10.1042/BJ20112180

    PubMed  Google Scholar 

  37. Douglas LM, Wang HX, Keppler-Ross S, Dean N, Konopka JB (2012) MBio 3:e00254–11. doi:10.1128/mBio.00254-11

  38. Ding C, Festa RA, Chen YL, Espart A, Palacios O, Espin J, Capdevila M, Atrian S, Heitman J, Thiele DJ (2013) Cell Host Microbe 13:265–276. doi:10.1016/j.chom.2013.02.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wolschendorf F, Ackart D, Shrestha TB, Hascall-Dove L, Nolan S, Lamichhane G, Wang Y, Bossmann SH, Basaraba RJ, Niederweis M (2011) Proc Natl Acad Sci USA 108:1621–1626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Darwin KH (2015) J Biol Chem 290:18962–18966. doi:10.1074/jbc.R115.640193

    Article  CAS  PubMed  Google Scholar 

  41. Shi X, Festa RA, Ioerger TR, Butler-Wu S, Sacchettini JC, Darwin KH, Samanovic MI (2014) MBio 5:e00876–13. doi:10.1128/mBio.00876-13

  42. Johnson MD, Kehl-Fie TE, Klein R, Kelly J, Burnham C, Mann B, Rosch JW (2015) Infect Immun 83:1684–1694. doi:10.1128/IAI.03015-14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ilback NG, Frisk P, Tallkvist J, Gadhasson IL, Blomberg J, Friman G (2008) J Trace Elem Med Biol 22:120–130. doi:10.1016/j.jtemb.2007.12.001

    Article  PubMed  Google Scholar 

  44. Cernat RI, Mihaescu T, Vornicu M, Vione D, Olariu RI, Arsene C (2011) Int J Tuberc Lung Dis 15:1239–1245, i doi:10.5588/ijtld.10.0445

  45. Li CX, Gleason JE, Zhang SX, Bruno VM, Cormack BP, Culotta VC (2015) Proc Natl Acad Sci USA 112:E5336–E5342. doi:10.1073/pnas.1513447112

    Article  CAS  PubMed  Google Scholar 

  46. Milanino R, Buchner V (2006) Rev Environ Health 21:153–215

    Article  CAS  PubMed  Google Scholar 

  47. Kosman DJ (2010) J Biol Inorg Chem 15:15–28. doi:10.1007/s00775-009-0590-9

    Article  CAS  PubMed  Google Scholar 

  48. Hellman NE, Gitlin JD (2002) Annu Rev Nutr 22:439–458

    Article  CAS  PubMed  Google Scholar 

  49. Roeser HP, Lee GR, Nacht S, Cartwright GE (1970) J. Clin Invest 49:2408–2417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Nittis T, Gitlin JD (2002) Semin Hematol 39:282–289 (pii:S0037196302500718)

    Article  CAS  PubMed  Google Scholar 

  51. Harris ZL, Durley AP, Man TK, Gitlin JD (1999) Proc Natl Acad Sci USA 96:10812–10817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Eckersall PD, Saini PK, McComb C (1996) Vet Immunol Immunopathol 51:377–385

    Article  CAS  PubMed  Google Scholar 

  53. Novikova I, Zlotnikova M (2011) Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 155:361–366. doi:10.5507/bp.2011.051

    Article  CAS  PubMed  Google Scholar 

  54. Kocyigit A, Erel O, Gurel MS, Avci S, Aktepe N (1998) Biol Trace Elem Res 65:271–281. doi:10.1007/BF02789102

    Article  CAS  PubMed  Google Scholar 

  55. Lee SH, Lancey R, Montaser A, Madani N, Linder MC (1993) Proc Soc Exp Biol Med 203:428–439

    Article  CAS  PubMed  Google Scholar 

  56. Kataoka M, Tavassoli M (1985) Exp Hematol 13:806–810

    CAS  PubMed  Google Scholar 

  57. Hellman NE, Kono S, Mancini GM, Hoogeboom AJ, De Jong GJ, Gitlin JD (2002) J Biol Chem 277:46632–46638. doi:10.1074/jbc.M206246200

    Article  CAS  PubMed  Google Scholar 

  58. Solioz M, Abicht HK, Mermod M, Mancini S (2010) J Biol Inorg Chem 15:3–14. doi:10.1007/s00775-009-0588-3

    Article  CAS  PubMed  Google Scholar 

  59. Smith AT, Smith KP, Rosenzweig AC (2014) J Biol Inorg Chem 19:947–960. doi:10.1007/s00775-014-1129-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Rensing C, McDevitt SF (2013) Metal Ions Life Sci 12:417–450. doi:10.1007/978-94-007-5561-1_12

    Article  Google Scholar 

  61. Nies DH, Herzberg M (2013) Mol Microbiol 87:447–454. doi:10.1111/mmi.12123

    Article  CAS  PubMed  Google Scholar 

  62. Harrison MD, Jones CE, Dameron CT (1999) J Biol Inorg Chem 4:145–153

    Article  CAS  PubMed  Google Scholar 

  63. O’Halloran TV, Culotta VC (2000) J Biol Chem 275:25057–25060

    Article  PubMed  Google Scholar 

  64. Nevitt T, Ohrvik H, Thiele DJ (2012) Biochim Biophys Acta 1823:1580–1593. doi:10.1016/j.bbamcr.2012.02.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Lutsenko S (2010) Curr Opin Chem Biol 14:211–217. doi:10.1016/j.cbpa.2010.01.003

    Article  CAS  PubMed  Google Scholar 

  66. Boal AK, Rosenzweig AC (2009) Chem Rev 109:4760–4779. doi:10.1021/cr900104z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Luk E, Jensen LT, Culotta VC (2003) J Biol Inorg Chem 8:803–809

    Article  CAS  PubMed  Google Scholar 

  68. Elam JS, Thomas ST, Holloway SP, Taylor AB, Hart PJ (2002) Adv Protein Chem 60:151–219

    Article  CAS  PubMed  Google Scholar 

  69. Robinson NJ, Winge DR (2010) Annu Rev Biochem 79:537–562. doi: 10.1146/annurev-biochem-030409-143539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Brown KR, Keller GL, Pickering IJ, Harris HH, George GN, Winge DR (2002) Biochemistry 41:6469–6476

    Article  CAS  PubMed  Google Scholar 

  71. Palacios O, Atrian S, Capdevila M (2011) J Biol Inorg Chem 16:991–1009. doi:10.1007/s00775-011-0827-2

    Article  CAS  PubMed  Google Scholar 

  72. Keller G, Bird A, Winge DR (2005) Eukaryot Cell 4:1863–1871. doi:10.1128/EC.4.11.1863-1871.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Gross C, Kelleher M, Iyer VR, Brown PO, Winge DR (2000) J Biol Chem 275:32310–32316

    Article  CAS  PubMed  Google Scholar 

  74. Weissman Z, Berdicevsky I, Cavari BZ, Kornitzer D (2000) Proc Natl Acad Sci USA 97:3520–3525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Schwartz JA, Olarte KT, Michalek JL, Jandu GS, Michel SL, Bruno VM (2013) Eukaryot Cell 12:954–961. doi:10.1128/EC.00344-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Marvin ME, Mason RP, Cashmore AM (2004) Microbiology 150:2197–2208. doi:10.1099/mic.0.27004-0

    Article  CAS  PubMed  Google Scholar 

  77. Woodacre A, Mason RP, Jeeves RE, Cashmore AM (2008) Microbiology 154:1502–1512. doi:10.1099/mic.0.2007/013441-0

    Article  CAS  PubMed  Google Scholar 

  78. Huh WK, Kang SO (2001) Biochem J 356:595–604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Lamarre C, LeMay JD, Deslauriers N, Bourbonnais Y (2001) J Biol Chem 276:43784–43791

    Article  CAS  PubMed  Google Scholar 

  80. Waterman SR, Hacham M, Hu G, Zhu X, Park YD, Shin S, Panepinto J, Valyi-Nagy T, Beam C, Husain S, Singh N, Williamson PR (2007) J Clin Invest 117:794–802. doi:10.1172/JCI30006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Waterman SR, Park YD, Raja M, Qiu J, Hammoud DA, O’Halloran TV, Williamson PR (2012) MBio 3:e00285–12. doi:10.1128/mBio.00285-12

  82. Ding C, Yin J, Tovar EM, Fitzpatrick DA, Higgins DG, Thiele DJ (2011) Mol Microbiol 81:1560–1576. doi:10.1111/j.1365-2958.2011.07794.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Raja MR, Waterman SR, Qiu J, Bleher R, Williamson PR, O’Halloran TV (2013) Metallomics 5:363–371. doi:10.1039/c3mt20220h

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Sun TS, Ju X, Gao HL, Wang T, Thiele DJ, Li JY, Wang ZY, Ding C (2014) Nat Commun 5:5550. doi:10.1038/ncomms6550

    Article  CAS  PubMed  Google Scholar 

  85. Moroz OV, Antson AA, Grist SJ, Maitland NJ, Dodson GG, Wilson KS, Lukanidin E, Bronstein IB (2003) Acta Crystallogr D Biol Crystallogr 59:859–867 (pii:S0907444903004700)

    Article  CAS  PubMed  Google Scholar 

  86. Kerkhoff C, Vogl T, Nacken W, Sopalla C, Sorg C (1999) FEBS Lett 460:134–138 (pii:S0014-5793(99)01322-8)

    Article  CAS  PubMed  Google Scholar 

  87. Asahi H, Tolba ME, Tanabe M, Sugano S, Abe K, Kawamoto F (2014) BMC Microbiol 14:167. doi:10.1186/1471-2180-14-167

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank Dr. Ryan Petersen for critical review of this manuscript. The preparation of this review was supported by NIH RO1 Grants AI 119949 and GM 50016 to VCC. A. Besold is supported by T32 CA009110.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Johns Hopkins University Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD, 21205, USA

    Angelique N. Besold, Edward M. Culbertson & Valeria C. Culotta

Authors
  1. Angelique N. Besold
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Edward M. Culbertson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Valeria C. Culotta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Valeria C. Culotta.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Besold, A.N., Culbertson, E.M. & Culotta, V.C. The Yin and Yang of copper during infection. J Biol Inorg Chem 21, 137–144 (2016). https://doi.org/10.1007/s00775-016-1335-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00775-016-1335-1

Keywords

Search

Navigation